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Interpretation of conventional karyotyping & ISCN Nomenclature in cytogenetics
Dr Mayur Parihar
Consultant Hematopathology and Cytogenetics
Tata Medical Center Kolkata
MBBS,MD (Path),FCCG(CMC Vellore)
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Cytogenetics• Cytogenetic analysis is an in vitro clinical
laboratory procedure that evaluates the chromosomes of a cell.
• Certain clinical characteristics occur consistently in association with a particular chromosome abnormality.
• This phenotype-karyotype correlation is useful.
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Methods for Identifying Chromosome Aberrations
• Detected using cytogenetic and molecular methods
chromosome bandingmolecular cytogenetics– Loss of heterozygosity – Microarrays
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Molecular Cytogenetics
• Powerful adjunct to conventional cytogenetic analysis
• Utilizes metaphases and non-mitotic interphase nuclei
• Can be applied to fixed archived tumour material
• Accurate, specific
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Molecular CytogeneticTechniques
• FISH
• Multi-Colour FISH (M-FISH)
• Spectral Karyotyping (SKY)
• Comparative Genomic Hybridization (CGH)
• Microarrays
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CytogeneticsKaryotyping
All chromosomes screened
Clonal Evolution
Locates areas that might contain critical genes involved in tumourigenesis
FISHSpecific part of a gene
or chromosome.
Does not screen all the chromosomes for abnormalities
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• In vitro clinical laboratory procedure that evaluates the chromosomes of a cell.
• Chromosomes are individually distinguishable under light microscopy only during cell division
• Spontaneously proliferating cells : bone marrow, lymph nodes, solid tumors and chorionic villi.
• Cultured : PB lymphocytes, tissue biopsies
Conventional Cytogenetics
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Specimen collection and handling Bone Marrow Aspirates
• Preservative free sodium heparin
• Transported at room temperature
• First few millilitres of the bone marrow tap contain the highest proportion of cells
• Processed without delay upon receipt to avoid cell death.
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GTG-banded karyotype: work flow
Ann Lab Med 2014;34:413-425
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Protocols have to be followed!!!
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What do you mean by bands/banding
A chromosome band is a part of a chromosome that can be distinguished from adjacent segments by appearing darker or lighter by one or more techniques.
Each chromosome has a unique pattern of light and dark bands
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Slide Making • Cell pellet dropped• Chromosome spreading depends upon
temperature, relative humidity, drying time• Has to be standardized each time
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Capturing
• Bone marrow : correlate with BM diagnosis, IPT
• Slides are screened, looking at all metaphases
• Microscopy chromosome count done of metaphases
• Look out for specific abnormalities
• 20 metaphases are captured and analysed
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Hyperdiploid Normal
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NORMAL HUMAN KARYOTYPE
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TerminologyParts of the chromosome
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ISCN
• International System for Human Cytogenetic Nomenclature
• Each area of chromosome given number
• Lowest number closest (proximal) to centromere
• Highest number at tips (distal) to centromere
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• In designating a particular band, 4 items are required 1.The chromosome number 2.The arm symbol 3.The region number and 4.The band number within that number.
• Ex: 1p31 indicates chromosome 1, short arm region3,band 1.
• According to ISCN the banding levels are varied by 400,550 and 880 levels with help of banding techniques
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Idiograms
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ISCN
• Normal male– 46,XY[20]
• Normal female– 46,XX[10]
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Numerical
• Aneuploidy– Autosomal trisomy, 47– Sex chromosomes, 45, 47, 48, 49
• Polyploidy– Whole chromosome set– Normal Human genome is diploid that is 46
chromosomes (23x2)– Triploidy, 69 (23x3)– Tetraploidy, 92 (23x4)
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Types of chromosome abnormalities
• Numerical– Aneuploidy (monosomy, trisomy, tetrasomy)– Polyploidy (triploidy, tetraploidy)
• Structural– Translocations– Inversions– Insertions– Deletions– Rings– Isochromosomes– ESAC
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A 2 year old girl diagnosed as Acute Leukemia 1 month back was referred to TMC for further management.
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• Fever • No history of any treatment• Hb :10.4,TLC:10,400,Platelets:2.5 lakhs• No immature cells/blasts in the peripheral
smear• Bone marrow examination : no evidence of
leukemia
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55,XX,+X,+6,+8,+10,+14,+17,+18,+22,+22 [1]
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CLONES• Clone is defined as a cell
population derived from a progenitor.
• The number of cells that constitute a clone is given in square brackets [ ] after the karyotype.
• Ex: 46,XX,t(8;21)(q22;q22)[20].
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Clone
• Two cells/metaphases for trisomy
• Three cells/metaphases for monosomy
• Two cells/metaphases for a structural abnormality
• The number of cells that constitute a clone is given in square brackets [ ] after the karyotype.
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FISH using ETV6/RUNX1 ES Probe
ETV6, Ch 12: RUNX1,Ch21:
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Precursor B cell ALL
Steroids the blasts dissapear
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45,XX,-7Specimen type : Heparinized Bone Marrow
Banding Resolution : 450 bphs
Cytogenetic Profile Metaphases Counted : 20
Metaphases Analyzed : 20
Metaphases Karyotyped : 8
Total Chromosome Number : 45/46
Autosomes : 44/45 Sex Chromosomes : 2(XY)
Clonal ???How many metaphases have -7?
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45,XX,-7[7]/46,XX[13]Specimen type : Heparinized Bone Marrow
Banding Resolution : 450 bphs
Cytogenetic Profile Metaphases Counted : 20
Metaphases Analyzed : 20
Metaphases Karyotyped : 8
Total Chromosome Number : 45/46
Autosomes : 44/45 Sex Chromosomes : 2(XY)
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45,XX,-7[1]/46,XX[19]
• Clonality not established .• The lab should record its observation saying
that monosomy 7 seen in a single metaphase/However, the clonality cannot be established
• Next step to do FISH for monosomy 7 to screen more number of cells.
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ISCN
• del - deletion
• dic - dicentric
• fra - fragile site• i -
isochromosome• inv - inversion
• p - short arm• r - ring
• der - derivative• dup - duplication• h -
heterochromatin• ins - insertion• mat - maternal origin• q - long arm• t - translocation
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Structural
• Breakage in at least 1 chromosome• Translocations
– 2 different chromosomes break and rejoin incorrectly• Inversions
– 2 breaks in same chromosome• Insertions
– Piece of chromosome inserted• Deletions
– Piece of chromosome missing
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Translocations• Exchange of chromosome
material between two chromosomes.
• Balanced : No gain or loss of genomic material
• Unbalanced : loss or gain of genomic material.
• Denoted by t(8;21), the smaller chromosome always written first.
• In case of unbalanced translocation the word derivative is used.
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46,XX,t(8;21)(q22;q22)[18]/46,XX[2]
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46,XY,t(1;19)(q23;p13),-9,i(9)(q10),+mar[15]/46,XY[5]
Balanced chromosome 1 and chromosome 19 translocation
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46,XY,t(9;22)(q34;q11.2),der(19)t(1;19)(q23;p13)[9]
Unbalanced translocation chromosome 1 and chromosome 19
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46,XY,+1,der(1;7)(q10;p10)[14]/46,XY[6]
Loss of 7q and partial trisomy for 1q
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A patient of CML on Imatinib not responding
46,XY,t(9;22)(q34;q11.2),+19,+der(22)t(9;22)[12]
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46,XY,t(8;17;21)(q22;q25;q22),del(9)(q13q33)[4]
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FISH showing 1F2R2GMetaphase FISH using dual colour dual fusion RUNX1/RUNX1T1 probe
Inverted DAPI
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Inversions
• Reversal of segment of chromosome– If too small cannot detect by karyotype – Very rare in humans– Selected against as would get reduced fertility
• Pericentric– reversed segment includes centromere
• Paracentric– within one chromosome arm
• Paracentric inversion – main difference in karyotypes of great apes and
humans so important in evolution
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Inversion
Reversal of segment of chromosome
• If too small cannot detect by karyotype
• Pericentric– reversed segment includes
centromere• Paracentric
– within one chromosome arm
– main difference in karyotypes of great apes and humans so important in evolution
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47,XX,inv(16)(p13q22)
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46,XY,inv(3)(q21q26)[17]
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Insertions
• Segment of 1 chromosome inserted into another
A derA der B
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Deletions• Terminal
– loss of end of chromosome– 46,XY,del(20)(q26) missing
long arm of 10• Interstitial
– loss of segment from within chromosome
– 46,XY,del(10)(q24q26) missing segment of 10
• All result in unbalanced karyotype
• Partial monosomy• Serious clinical effect
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A patient of MDS
46,XY,del(20)(q11.2)[18]
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A patient of MDS
46,XY,del(5)(q13q33)[16]
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46,XY,t(4;7)(q22;p22),del(7)(q21q33),dic(9;12)(p12;p11)[14]
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Isochromosome
• Two copies of the same arm
• Mirror image around centromere
• Centromeres part in wrong plane
– Monosomy for 1 chromosome arm
– Trisomy for the other arm
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A patient of ALL.Isochromosome 9qloss of 9p that houses the PAX5 gene and CDKN
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A patient of CML in blast crisis.Isochromosome 17qloss of 17p that houses the Tp53 gene
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46,XY,dup(1)(q21q32),t(-;-)
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Questionable Identification46,XY,?t(11;19)(q23;p13)
Metaphase FISH using MLL break apart
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Clones and subclonesA patient of CML ?blast crisis
46,XX,t(9;22)(q34;q11.2)[9]/46,idem,inv(16)(p13q22)[8]/46,XX[3]
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Clones and subclonesA patient of CML ?blast crisis
46,XY,t(9;22)(q34;q11.2)[6]/47,idem,+8[14]
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Clones and subclonesA patient of AML
46,XX,t(8;21)(q22;q22)[8]/45,X,-X,t(8;21)(q22;q22)t(17;17)(q11.2q25)[12]
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A patient of CML on follow up not responding
46,XY,t(9;22)(q34;q11.2)[14]/47,XY,+8[2]/46,XY[4]
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Complex Karyotype• Complex karyotype is defined as presence of
three or more cytogenetic abnormalities in bone marrow not including inv(16), t(16;16), t(8;21), and t(15;17) by most of the groups
Slovak ML: German Acute Myeloid Leukemia Intergroup,Byrd JC: CALGB, Schlenk RF: SWOG;
• The MRC multicenter trial defined complex karyotype as presence of 5 or more chromosomal aberrations.
Grimwade D: MRC
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The monosomal karyotype was defined by the presence of two autosomal monosmies or one single monosomy (excluding isolated loss of X or Y) in association with a structural chromosome abnormality.
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Patient with AML
45,XY,inv(3)(q21q26),-7[18]/46,XY[2]
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Patient with AML
45,XX,-7,t(11;17)(q23;q12)[14]/46,XX[6]
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55~ 57,XX,+X,+6,+8,+10,+14,+17,+18,+22,+22 [CP10]/46,XX[10]
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Composite Karyotype
• Multiple clones and subclones may be present
• Karyotypic heterogeneity
• Contains all clonally occurring abnormalities
• Gives range of modal chromosomal number
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56,XXYC,+X,+4,+5,+6,+8,t(9;22)(q34;q11.2),+12,+14,+18,+21,+der(21)t(9;22)[CP14] /46,XXY[6]
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A patient of AML with aberrant CD1946,XY[20] nuc.ish (RUNX1x3)(RUNX1T1x3)(RUNX1conRUNX1T1x2)[190/200]
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Karyotyping results Post Transplant
46,XY,der(11)dup(11)(q14q22)t(11;22)(q24;q11.2)[6]//46,XX[14]
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Conclude
• Look for clonality of the abnormalities• In case clonality not established used other
complimentary tests like FISH.• Correlate the karyotype findings with clinical
picture,morphology, IPT findings, other test reports.
• Communication with other members of the team essential across specialities.
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The Cytogenetics team at the Tata Medical Center
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THANK YOU